Chapter 14 Signaling Pathways that Control Gene Ac

Thedevelopmentofallorganismsrequiresexecutionofacomplexprogramwherebyspecificgenesareacti-vatedandrepressedinspecificsetsofcellsandinapre-cisetimesequence.Manydevelopmentalchangesingeneexpressionaregeneratedbyextracellularsignalingmoleculesthatactoncell-surfacereceptors.Mostofthesesignalsaresoluble,secretedfactorsthatactinaparacrinefashiononre-ceiving(target)cellsnearthereleasingcell.However,somesignalingproteinsarethemselvesattachedtothecellsurface,wheretheyinteractwithcell-surfacereceptorsonadjacentcellstoalterthereceivingcell’spatternofgeneexpression.Evenmaturecellsthatarepartofadifferentiatedtissueconstantlychangetheirpatternsofgeneexpression.Inlargemeasurethisoccursbecauseofmanydifferentcell-surfacere-ceptorsthatcontinuallyreceiveinformationfromextracellu-larsignalsandtransducethisinformationintoactivationofspecifictranscriptionfactorsthatstimulateorrepressex-pressionofspecifictargetgenes.Manysuchsignalingpath-waysleadtoalterationsinthecell’smetabolicactivities.Liver,forexample,respondstofluctuationsinthelevelsofmanyhormones(e.g.,insulin,glucagon,andepinephrine)byalteringexpressionofmanygenesencodingenzymesofglu-coseandfatmetabolism.Othersignalingpathwaysinfluencethelevelsofproteinsthataffecttheabilityofcellstoprogressthroughthecellcycleanddivide.Atypicalmammaliancelloftenexpressescell-surfacere-ceptorsformorethan100differenttypesofextracellularsig-nalingmoleculesthatfunctionprimarilytoregulatetheactivityoftranscriptionfactors(seeFigure13-1).Thesignal-inducedactivationoftranscriptionfactorsoccursbyseveralmechanisms.Inthelastchapter,forinstance,wesawthatstimulationofsomeGprotein–coupledreceptorsleadstoariseincAMPandthecAMP-dependentactivationofproteinkinaseA.Aftertranslocatingtothenucleus,proteinkinaseAphosphorylatesandtherebyactivatestheCREBtranscriptionfactor.Inthischapter,wefocusonfiveotherclassesofcell-surfacereceptorsthatillustrateadditionalsignal-inducedmechanismsofactivatingtranscriptionfactors.Stimulationoftransforminggrowthfactor
(TGF
)receptorsandcy-tokinereceptorsleadsdirectlytoactivationofcytosolictran-scriptionfactorsastheresultofphosphorylationbyakinasethatispartofthereceptororassociatedwithit.Theacti-vatedtranscriptionfactorsthentranslocateintothenucleusandactonspecifictargetgenes.Inthecaseofreceptor14highlowFluorescenceresonanceenergytransfer(FRET)detectstimeandlocationofactivationofRasproteininlivecellstriggeredbyepidermalgrowthfactor.[MichiyukiMatsuda,ResearchInstituteforMicrobialDiseases,OsakaUniversity.]SIGNALINGPATHWAYSTHATCONTROLGENEACTIVITY571OUTLINE14.1TGF
ReceptorsandtheDirectActivationofSmads14.2CytokineReceptorsandtheJAK-STATPathway14.3ReceptorTyrosineKinasesandActivationofRas14.4MAPKinasePathways14.5PhosphoinositidesasSignalTransducers14.6PathwaysThatInvolveSignal-InducedProteinCleavage14.7Down-ModulationofReceptorSignaling572CHAPTER14•SignalingPathwaysThatControlGeneActivityTABLE14-1OverviewofMajorReceptorClassesandSignalingPathwaysReceptorClass/Pathway*DistinguishingCharacteristicsRECEPTORSLINKEDTOTRIMERICGPROTEINSGprotein–coupledreceptors(13)Ligands:Epinephrine,glucagon,serotonin,vasopressin,ACTH,adenosine,andmanyothers(mammals);odorantmolecules,light;matingfactors(yeast)Receptors:Seventransmembrane
helices;cytosolicdomainassociatedwithamembrane-tetheredtrimericGproteinSignaltransduction:(1)Second-messengerpathwaysinvolvingcAMPorIP3/DAG;(2)linkedionchannels;(3)MAPkinasepathwayRECEPTORSWITHINTRINSICORASSOCIATEDENZYMATICACTIVITYTGFreceptors(14,15)Ligands:Transforminggrowthfactorsuperfamily(TGF,BMPs),activin,inhibins(mammals);Dpp(Drosophila)Receptors:Intrinsicproteinserine/threoninekinaseactivityincytosolicdomain(typeIandII)Signaltransduction:DirectactivationofcytosolicSmadtranscriptionfactorsCytokinereceptors(14,15)Ligands:Interferons,erythropoietin,growthhormone,someinterleukins(IL-2,IL-4),othercytokinesReceptors:Singletransmembrane
helix;conservedmulti-strandfoldinextracellulardomain;JAKkinaseassociatedwithintracellulardomainSignaltransduction:(1)DirectactivationofcytosolicSTATtranscriptionfactors;(2)PI-3kinasepathway;(3)IP3/DAGpathway;(4)Ras-MAPkinasepathwayReceptortyrosinekinases(14)Ligands:Insulin,epidermalgrowthfactor(EGF),fibroblastgrowthfactor(FGF),neurotrophins,othergrowthfactorsReceptor:Singletransmembrane
helix;intrinsicproteintyrosinekinaseactivityincytosolicdomainSignaltransduction:(1)Ras–MAPkinasepathway;(2)IP3/DAGpathway;(3)PI-3kinasepathwayReceptorguanylylcyclases(13)Ligands:AtrialnatriureticfactorandrelatedpeptidehormonesReceptor:Singletransmembrane
helix;intrinsicguanylatecyclaseactivityincytosolicdomainSignaltransduction:GenerationofcGMPReceptorphosphotyrosineLigands:Pleiotrophins,otherproteinhormonesphosphatasesReceptors:IntrinsicphosphotyrosinephosphataseactivityincytosolicdomaininhibitedbyligandbindingSignaltransduction:HydrolysisofactivatingphosphotyrosineresidueoncytosolicproteintyrosinekinasesT-cellreceptorsLigands:Smallpeptidesassociatedwithmajorhistocompatability(MHC)proteinsintheplasmamembraneofmacrophagesandotherantigen-presentingcellsRecepto